In recent years, there has been an increasing interest in the role of the microbiome on human health and disease. Along with this interest, the need for methodological guidance on how to best study the microbiome and its relationship to antibiotic resistance is growing. High-throughput metagenomic sequencing is a powerful tool for investigating the microbiome, and it is becoming increasingly used in clinical research. This review summarizes the existing literature on clinical metagenomics and antimicrobial resistance research and provides guidelines on how to design and conduct studies using this technology. We also discuss some of the challenges and limitations of clinical metagenomics research and suggest future directions for this rapidly evolving field.